Emphysema is a major cause of death and disability in the United States and currently afflicts approximately 2 million people. Each year, this chronic lung disease causes or contributes to 100,000 deaths and costs more than $2.5 billion in health care expenses. Since it was reported centuries ago, an enormous effort has been directed towards fighting this devastating disease. Emphysema is a major form of chronic obstructive pulmonary disease (COPD) and is characterized by destruction of the alveolar wall, permanent enlargement of the airspaces and loss of lung recoil capability. Cigarette smoking is by far the single most important etiological factor of emphysema. Clinically, α1-antitrypsin (α1-AT) deficiency directly relates to and predisposes to the disease. Since about 40 years ago, the imbalance between protease and anti-protease activities, and its association with pulmonary inflammation has been a prevailing hypothesis for explaining the pathogenesis of emphysema. It suggests that elastolytic proteinases derived primarily from inflammatory cells (e.g. neutrophils and macrophages) overplays/outplays their counterparts—antiproteinases, and cause proteolytic destruction of the alveolar wall. Further, proteolysis and inflammation interact with each other in a positive feedback manner, causing further damage to the alveoli and ultimately result in emphysema. More recently, the importance of pulmonary vascular endothelial cells and apoptosis in the pathogenesis of emphysema were also proposed, which was supported by the so-called non-inflammation emphysema model induced by chronic blockade of vascular endothelial growth factor receptor-2 (VEGF-R2). To date, the treatments for emphysema are primarily focused on halting the progressive processes or palliating the symptoms of the diseases, such as by using antibiotics, steroids, bronchodilators and protease inhibitors, with little evidence that they either alter the natural history of the disease or reduce mortality. Cessation of smoking is the only effective way to alter the rate of progression of emphysema; however, for many patients, the disease still persists long after smoking is stopped. Since the disease is unstoppable by medical intervention at the time of diagnosis, surgery seems to be the only intervention for the disease. Lung volume reduction surgery (LVRS) improves exercise capacity and yields a survival advantage for patients with predominantly upper-lobe emphysema and low base-line exercise capacity; however, it also increases mortality and offers negligible functional gain for other patients with non-upper lobe emphysema and high base-line exercise capacity. Overall, there is no significant difference of risk ratio between LVRS and conventional medical treatment over the entire emphysema patient population, as analyzed by the National Emphysema Treatment Trial Research Group. In addition, a review of pathologic specimens from LRVS patients raised the concern about the potential risk of carcinoma. The possibility of lung transplant is also limited by the availability of lung donors, and potential risks of infection and rejection. In summary, current treatments for emphysema are very limited, and more effective treatments are urgently needed.
Recently, therapeutic strategies that are based on regenerative biomedicine offer new approaches to a better treatment for emphysema. In particular, focus on the regeneration of damaged alveoli and restoration of impaired respiratory function in the emphysematous lung, rather than on halting the damaging processes alone, is a new rationale for therapeutic intervention. There are several factors that participate in regulating lung development and regeneration processes. Among these factors, all-trans retinoic acid (ATRA), vascular endothelial growth factor (VEGF) and hepatocyte growth factor/scatter factor (HGF or SF) are the focus of much current attention. Alterations in the gene expression and function of these factors have been identified in emphysema patients, indicating their clinical relevance to human emphysema, and furthermore, therapies focused on these targets in animal models of emphysema have demonstrated some success.
The biological activities of hepatocyte growth factor (HGF; also known as scatter factor) are mediated through activating its receptor c-Met and down-stream signaling therefrom, e.g. Erk/MAPK, PI3K/Akt, and STAT3 pathways. HGF is normally expressed in lung, and is essential for lung development and maintenance, e.g., as a morphogenic factor during fetal lung development, and is required for alveolarization in neonatal mice. HGF also promotes compensatory lung growth post pneumonectomy. HGF responds in an acute-phase like manner to various lung injuries including pulmonary ischemia, HCl-induced acute lung injury, and P. aeruginosa pneumonia. HGF is a pulmotropic factor for lung regeneration by promoting proliferation of alveolar type II and bronchial epithelial cells and pulmonary endothelial cells as well. HGF increases capillary density via therapeutic angiogenesis. PI3K/Akt and partially MAPK1/2 pathways induced by HGF are implicated in eNOS-mediated angiogenesis. HGF also induces angiogenesis in the elastase-injured lung through mobilizing endothelial progenitor cells and inducing them differentiation into capillary endothelial cells. In addition, HGF protects against oxidative stress-induced apoptosis in lung epithelial cells.
It is towards the treatment of various chronic obstructive pulmonary diseases such as emphysema by addressing the beneficial HGF mechanisms that the present invention is directed.